Canine distemper is a common viral infection among domestic dogs, which is caused by the canine distemper virus and occurs as a highly infectious, acute or subacute febrile disease. The disease produces high morbidity and mortality (Bush Mitchell, Montali R J, Brownstein D, James A E, Appel M J G. Vaccine-induced canine distemper in lesser panda. JAVMA 1976, 169:959-960).
Canine distemper virus (CDV) belongs to the genus Morbillivirus that is part of the family Paramyxovirus (Pringle C R, Paramyxoviridae, Classification and nomenclature of viruses. Arch Virol, 1992, 242-246).
CDV is a negative single-stranded RNA virus, and the genome consists of about 16,000 nucleotides (Bernard N F, David N K and Peter M H, Fields virology 3rd ed. Lippincott Raven Publishers, Philadelphia, 1996, 1177-1204).
CDV has a spherical or filamentous shape and a size ranging from 100 to 700 nm, and contains three nucleocapsid-associated proteins:, nucleocapsid protein (NP), phosphoprotein (P) and large protein (L). The distemper virus further contains matrix protein (M), fusion protein (F) and attachment protein (H) (Appel MJCT, Canine distemper virus, In: Virus infections of carnivors. Elsevier Science Publisher, Amsterdam, 1987, 1:133-159).
Infection with CDV occurs mainly through the respiratory route. After being ingested macrophages in the respiratory tract, the inhaled virus is carried to local lymph nodes by the macrophages and, within several days, spreads to all the lymphatic tissues while causing necrosis in the lymphatic tissues, thereby resulting in immuno-suppression and demyelinating encephalitis leading to epileptiform convulsion (Cornwell H J C, Thomson H, McCandlish I A P, Macartney L and Nash A S, 1988, Encephalitis in dogs associated with a batch of canine distemper (Rockborn) vaccine, Veterinary record, 112:54-59).
Canine distemper is characterized by a variety of clinical signs. In the first stage of CDV, four to six days after exposure to CDV, a fever of up to 39.5° C. to 41.0° C. develops along with depression, anorexia and oculo-nasal discharge. However, these symptoms disappear after two or three days. In the second stage of CDV that begins at two to fourteen days after the fever subsides caused by the viral infection, the fever recurs, which is accompanied by other clinical signs. The most predominant in the second stage are catarrhal symptoms in gastrointestinal and/or respiratory mucous membranes, often along with signs of brain involvement.
The gastrointestinal signs include loss of appetite and vomiting, while the respiratory signs include dry nose, sneezing, mucoid or mucopurulent nasal discharge, coughing and difficulty breathing. The urinary signs include renal pain resulting from nephritis. The major neurological signs are CNS signs resulting from non-suppurative encephalitis. The neurological sings such as hyperesthesia, epileptic fit, circling and paroxysm occur in a seizure-like manner. The seizures develop for a short time several times a day. Also, the frequency of the seizures increases as the disease progresses.
Conventionally, the fever was suppressed by the use of an antipyretic, an immunomodulator (e.g., zymosol, B.S.K), etc. However, such therapy was demonstrated to be ineffective, and clinical symptoms became more severe by remittent fever. In this case, most dogs died from neurological complications such as seizures. On the other hand, the immune serum therapy in which an immune serum is intravenously drip-infused at a mixed state with 5% glucose or directly intravenously administered has an effect of alleviating the early symptoms of the measles. However, after four or five days, the disease recurs very frequently, and, in this case, the immune serum therapy is not effective. In addition, if the immune serum contains blood-derived impurities by incomplete centrifugation, the immune serum therapy may cause animals treated to fall into a coma, and thus, has an unsatisfactory treatment success rate of about 20%. In particular, if the animals develop neurological signs, the above methods no longer have therapeutic efficacy, and thus, the animals eventually die.
Therefore, there is a need for the development of therapeutic agents capable of effectively alleviating the symptoms during the whole CMV infection period ranging from the early phase to the terminal phase.